73 articles - From Saturday Apr 09 2022 to Friday Apr 15 2022
Guidelines, position statements, white papers, technical reviews, consensus statements, etc…
meta-analyses and systematic reviews
| Blood Cancer J |
RCT, clinical trials, retrospective studies, etc…
| Am J Hematol |
Urgent Cytoreduction for Newly Diagnosed AML patients Allows Acquisition of Pretreatment Genomic Data and Enrollment on Investigational Clinical Trials. There was no significant difference in overall survival (OS) between in CytoRed group compared to NoCytoRed group (Hazard ratio 0.97, 95% CI 0.70-1.37, p=.879). Results were unchanged after stratification by age (< or = |
| Ann Oncol |
Modified Glasgow prognostic score (mGPS) is correlated with sarcopenia and dominates the prognostic role of baseline body composition parameters in advanced gastric and esophagogastric junction cancer patients undergoing first-line treatment from the phase III EXPAND trial. Our findings support a model where tumor-mediated inflammatory response represents a strong prognostic factor, which is causally related to sarcopenia, but with no direct causal path from sarcopenia to survival. Therefore, therapeutic targeting of systemic inflammation should be further explored as a promising strategy to improve both sarcopenia and the efficacy and tolerability of cancer treatment. |
The age-dependent association of risk factors with pancreatic cancer. Established risk factors are more strongly associated with earlier-onset pancreatic cancer, emphasizing the importance of age at initiation for cancer prevention and control programs targeting this highly lethal malignancy. |
| Blood |
BMP2/SMAD pathway activation in JAK2/p53-mutant Megakaryocyte/Erythroid Progenitors Promotes Leukemic Transformation. Finally, we identify that Jak2/Trp53 mutant PEL is characterized by recurrent copy number alterations and DNA damage. Using a synthetic-lethality strategy, by targeting active DNA-repair pathways, we demonstrate that this PEL is highly sensitive to combination WEE1 and PARP inhibition. These observations yield new mechanistic insights into the process of p53 mutant LT, and offer new, clinically-translatable therapeutic approaches. |
CD34+CD19-CD22+ B-cell progenitors might underlie phenotypic escape in patients treated with CD19-directed therapies. FISH analysis in flow-sorted populations and xenograft modeling revealed that CD34+CD19-CD22+ cells harbor the genetic abnormalities present at diagnosis and initiate leukemogenesis in vivo. Our data suggest that pre-leukemic CD34+CD19-CD22+ progenitors may underlie phenotypic escape after CD19-directed immunotherapies and reinforce ongoing clinical studies aimed at CD19/CD22 dual-targeting as a strategy to reduce CD19- relapses. The implementation of such CD34/CD19/CD22 immunophenotyping in clinical laboratories for initial diagnosis and subsequent monitoring of B-ALL patients during CD19-targeted therapy is encouraged. |
First study of extended half-life rFVIIIFc in previously untreated patients with hemophilia A: PUPs A-LONG final results. In this study of rFVIIIFc in pediatric PUPs with severe hemophilia A, overall inhibitor development was within expected range, although high-titer inhibitor development was on the low end of the range reported in literature. rFVIIIFc was well-tolerated and effective as prophylaxis and for treatment of bleeds. This trial is registered at (NCT02234323). |
How We Prevent GVHD in High Risk Patients: Post Transplant Cyclophosphamide and Beyond. Its success has led investigators to explore PTCy's utility for HLA-matched HCT, where we predict it will be embraced as well. Additionally, combinations of promising new agents for GVHD prophylaxis such as abatacept and JAK inhibitors with PTCy inspire hope for an even safer transplant platform. Using three illustrative cases, we review our current approach to transplantation of patients at high risk of GVHD using our modern armamentarium. |
Long-Term Follow-up of Liver-Directed, Adeno-Associated Vector-Mediated Gene Therapy in the Canine Model of Hemophilia A. Post-mortem examination demonstrated no evidence of chronic liver disease (cirrhosis or fibrosis) or liver malignancy. Persistent liver-derived FVIII expression with improvement in the bleeding phenotype was seen for more than a decade after a single AAV-BDD-cFVIII infusion. This is the longest follow-up to date reported in a pre-clinical model supporting long-term efficacy and safety of AAV-mediated gene therapy. |
T-cell redirecting bispecific antibodies in multiple myeloma: a revolution? Bispecific antibodies are designed to link a surface target molecule on the malignant plasma cells to CD3 on T-cells and thereby redirect activated T-cells to induce tumor cell death. Early-phase clinical trials targeting B-cell maturation antigen, GPRC5D or FcRH5, have demonstrated a favorable safety profile and promising efficacy data in triple-class refractory multiple myeloma. This novel immunotherapeutic modality will likely change the treatment paradigm in the coming years. |
TINF2 as a potential therapeutic approach to restore telomere length in dyskeratosis congenita. Similarly, we introduced TIN2-DC disease variants in human HSPCs to assess the changes in telomere length and proliferative capacity. Lastly, we showed that editing at exon 2 of TINF2 that restored telomere length in hESCs could be generated in TINF2-DC patient HSPCs. Our study demonstrates a simple genetic intervention that rescues the TIN2-DC disease phenotype in stem cells and provides a versatile platform to assess the efficacy of potential therapeutic approaches in vivo. |
TP53 Copy Number and Protein Expression Inform Mutation Status across Risk Categories in Acute Myeloid Leukemia. Protein expression of p53 by immunohistochemistry informed mutation status irrespective of TP53 CN status. Genomic analysis of co-mutations in TP53-mutant AML showed a muted landscape that encompassed primarily mutations in genes involved in epigenetic regulation (DNMT3A and TET2), RAS/MAPK signaling (NF1, KRAS/NRAS, PTPN11), and RNA splicing (SRSF2). In summary, our data provides a rationale to refine risk stratification of AML patients on the basis of integrated molecular and protein-level TP53 analyses. |
| Blood Adv |
A complex proinflammatory cascade mediates the activation of HSCs upon LPS exposure in vivo. This response was not only mediated via direct LPS-TLR4 conjugation on HSCs, but also involved indirect TLR4 signaling in CD115+ monocytic cells, inducing a complex pro-inflammatory cytokine cascade in the bone marrow. Downstream of LPS-TLR4 signaling, the combined action of pro-inflammatory cytokines such as IFNa, IFN |
A gain-of-function variant in the Wiskott-Aldrich syndrome gene is associated with a MYH9-related disease-like syndrome. I294T) that segregates with the disease and is already known to cause XLN. There was no pathogenic variant in MYH9, TUBB1, or ACTN1. This is the first report of a WAS gain-of-function variant associated with both the hematological phenotype of XLN (neutropenia, macrothrombocytopenia) and renal disease (proteinuria, renal failure) with glomerular tip lesion hyalinosis and actin condensations in effaced podocytes foot processes. |
A Single-Arm, Long-Term Efficacy and Safety Study of Subcutaneous Romiplostim in Children with Immune Thrombocytopenia. This phase 3b, single-arm, multicenter study investigated long term efficacy/safety of romiplostim in children >/=1- /=3 bleeding events occurred in 20 (9.9%). At year 2, 8/63 evaluable patients (12.7%) had grade 2 reticulin. Long-term romiplostim resulted in sustained on-treatment platelet responses with an overall safety profile consistent with previous studies. |
ABO blood group type and risk of venous thromboembolism in patients with cancer. This association was weakened after adjustment for factor VIII. Non-O blood type is a time-dependent predictor of VTE in cancer patients. It is associated with increased VTE risk beyond 3 months of follow-up and in patients with intermediate and low-risk tumor types. |
Assessment of Safety and Immunogenicity of MHC homozygous iPSC-derived CD34+ Hematopoietic Progenitors in a NHP Model. We demonstrated that infusing iHPs is well-tolerated and safe, observing no teratomas or tumors in the MCMs up to one year after HSC transplant and iHP infusion. Importantly, the iHPs also did not induce significant levels of alloantibodies in MHC-matched or -mismatched immunocompetent MCMs, even after increasing MHC expression on iHPs with IFN |
Blocking human protein C anticoagulant activity improves clotting defects of hemophilia mice expressing human protein C. Additionally, we found that HAPC1573 significantly improved the thrombin generation of PROC+/+;F8-/- mice but not F8-/- mice, indicating that HAPC1573 enhanced the coagulant activity of hemophilia mice by modulating human APC in vivo. We further documented that HAPC1573 inhibited the APC anticoagulant activity to improve the clotting time of human plasma deficient of FVIII, FIX, FXI, FVII, VWF, FV, or FX. These results demonstrate that selectively blocking the anticoagulant activity of human APC may be an effective therapeutic and/or prophylactic approach for bleeding disorders lacking FVIII, FIX, or other clotting factors. |
Bone marrow stroma cells promote induction of a chemoresistant and prognostic unfavorable S100A8/A9high AML cell subset. This S100A8/A9high AML cell population displayed an enhanced utilization of free fatty acids, features of a more mature myeloid phenotype, and increased resilience towards chemotherapeutics and BCL2 inhibition. We could identify stromal cell-derived interleukin-6 (IL-6) as the trigger for a Jak/STAT3 signaling-mediated S100A8/A9 induction. Interfering with fatty acid uptake and the IL-6-Jak/STAT3 pathway antagonized formation of S100A8/A9high cells and therapeutic resistance, which could have therapeutic implications as a strategy to interfere with the AML-niche dynamics. |
Cell Origin-Dependent Cooperativity of Mutant Dnmt3a and Npm1 in Clonal Hematopoiesis and Myeloid Malignancy. These promoters were enriched for cell cycling, PI3K/AKT/mTOR signaling, stem cell signatures, and targets of transcription factors including NFAT and the chromatin binding factor HMGB1, which have been implicated in human AML. These results demonstrate cooperativity between pre-existing Dnmt3aR878H and Npm1cA at the chromatin level, where specific loci altered in accessibility by Npm1cA are dependent on cell context as well as Dnmt3a mutation status. These findings have implications for biological understanding and therapeutic intervention into transformation from CH to AML. |
Extracellular vesicle proteomic analysis leads to the discovery of HDGF as a new factor in multiple myeloma biology. Metabolic analysis demonstrated that HDGF enhances the already high glycolytic levels of HMCLs and significantly lowers mitochondrial respiration, indicating that HDGF may play a role in myeloma cell survival and/or act in a paracrine manner on cells in the bone marrow tumor microenvironment. Indeed, HDGF polarizes macrophages to an M1-like phenotype, and phenotypically alters naive CD14+ monocytes to resemble myeloid-derived suppressor cells which are functionally suppressive. In summary, HDGF is a novel factor in MM biology, and may function to both maintain MM cell viability as well as modify the tumor microenvironment. |
Geriatric assessment for older adults receiving less intensive therapy for acute myeloid leukemia: Report of CALGB 361101. In multivariate analyses, greater comorbidity (Hematopoietic Cell Transplantation-specific Comorbidity Index >3), worse cognition (Blessed Orientation Memory Concentration score > 4), and lower European Organization for Research and Treatment of Cancer global QOL scores at baseline were significantly associated with shorter overall survival (OS) (p<0.05 each) after adjustment for Karnofsky Performance Status, age and treatment arm. Dependence in Instrumental Activities of Daily Living and cognitive impairment were associated with 6 month mortality (HR 3.5, CI 1.2-10.4, and HR 3.1 CI 1.1-8.6 respectively). GA measures evaluating comorbidity, cognition, and self-reported function were associated with survival and represent candidate measures for screening older adults planned to receive lower intensity AML therapies. |
Idasanutlin Plus Cytarabine in Relapsed or Refractory Acute Myeloid Leukemia: Results of the MIRROS Trial. The overall response rate (ORR) was 38.8% vs 22.0% (OR, 2.25; 95% CI, 1.36-3.72). Common any-grade adverse events (=10% incidence in any arm) were diarrhea (87.0% vs 32.9%), febrile neutropenia (52.8% vs 49.3%), and nausea (52.5% vs 31.5%). In summary, despite improved ORR, adding idasanutlin to cytarabine did not improve overall survival or CR rates in patients with R/R AML. |
MGUS and clonal hematopoiesis show unrelated clinical and biological trajectories in an older population cohort. We did not find a significant correlation between the presence of MGUS and CH. Furthermore, the 2 conditions showed a differential association with clinical and laboratory covariates, suggesting that MGUS and CH may represent age-associated unrelated clonal drifts of hematopoietic cells. Confirmatory studies are needed to assess the relevance of CH in plasma cell disorders. |
Outcomes following biochemical or clinical progression in patients with multiple myeloma. To conclude, patients with CP have inferior post-progression outcomes compared to patients with BP. Patients with deeper response to first line therapy are less likely to develop CP. The presence of a specific CRAB symptom at diagnosis predicts for the development of similar CRAB symptom at relapse. |
Patient-specific comorbidities as prognostic variables for survival in myelofibrosis. g., DIPSS) and other clinical and pathologic factors (e. g., comorbidities) in an unbiased fashion. The inclusion of comorbidities into risk evaluation may augment prognostic capability of future genetics-based scoring systems. |
Physiologically based serum ferritin thresholds for iron deficiency in women of reproductive age who are blood donors. S. National Health and Nutrition Examination Survey 2003-2018 (NHANES) (p=0.98 and 0.83, respectively). While international comparisons are needed, these results with US data provide additional evidence for the potential usefulness of a physiologically based method to identify serum ferritin thresholds for iron deficiency. |
Platelet-monocyte interaction amplifies thromboinflammation through tissue factor signaling in COVID-19. Platelet-monocyte interactions ex-vivo and in SARS-CoV-2 infection model in vitro reciprocally activated monocytes and platelets, inducing the heightened secretion of a wide panel of inflammatory mediators. We identified platelet adhesion as a primary signaling mechanism inducing mediator secretion and TF expression, while TF signaling played major roles in amplifying inflammation by inducing proinflammatory cytokines, especially TNF-a and IL-1ß. Our data identify platelet-induced TF expression and activity at the crossroad of coagulation and inflammation in severe COVID-19. |
Sézary syndrome patient-derived models allow drug selection for personalized therapy. In vitro data indicated that primary malignant SS cells al display different sensitivities against specific pathway inhibitors. In vivo validation using SS PDX mostly reproduced the responses to the HDAC inhibitor Panobinostat that was observed in vitro. Our investigations revealed the actual possibility of using high throughput in vitro testing followed by PDX in vivo validation for selective targeting of SS tumor cells in a patient-specific manner. |
Single-cell analysis of Sézary syndrome reveals novel markers and shifting gene profiles associated with treatment. In particular, the expression of AIRE was the most highly upregulated gene in our analysis, and AIRE protein expression could be observed over a variety of CTCLs. Furthermore, within a single patient, we were able to characterize differences in cell populations comparing malignant T cells over the course of treatment with histone deacetylase inhibition and photopheresis. New cellular clusters after progression on the therapy notably exhibited increased expression of the transcriptional factor FOXP3, a master regulator of regulatory T cell function, raising the potential implication of an evolving mechanism of immune evasion. |
Structural, functional, and immunogenicity implications of F9 gene recoding. Posttranslational modification analysis indicated that overexpression from gene recoding results in suboptimal posttranslational processing. Overall, our results highlight potential functional and immunogenicity concerns associated with gene recoded F9 products. These findings have general applicability and implications for other gene recoded recombinant proteins. |
Using Whole Genome Sequencing to Characterize Clinically Significant Blood Groups Among Healthy Older Australians. No clinically significant rare or novel variants were found associated with the genetically complex ABO blood group system. For the Rh blood group system, two novel and 15 rare variants were found. Our detailed blood group profiling results provide a starting point for the creation of an Australian blood group variant database. |
Zanubrutinib monotherapy in relapsed/refractory indolent non-Hodgkin lymphoma. After a median follow-up of 33.9 months, median PFS was 10.4 months. In conclusion, the results of this study suggest a favorable benefit-risk profile and support zanubrutinib as a potentially meaningful addition to available therapies for patients with relapsed/refractory MZL and FL. This study is registered on (NCT02343120). |
| Blood Cancer J |
Primary CD33-targeting CAR-NK cells for the treatment of acute myeloid leukemia. Here we report on the generation of CD33-targeted CAR-modified natural killer (NK) cells by transduction of blood-derived primary NK cells using baboon envelope pseudotyped lentiviral vectors (BaEV-LVs). Transduced cells displayed stable CAR-expression, unimpeded proliferation, and increased cytotoxic activity against CD33-positive OCI-AML2 and primary AML cells in vitro. Furthermore, CD33-CAR-NK cells strongly reduced leukemic burden and prevented bone marrow engraftment of leukemic cells in OCI-AML2 xenograft mouse models without observable side effects. |
Treatment and outcomes of patients with light chain amyloidosis who received a second line of therapy post autologous stem cell transplantation. The median OS was NR for the 2nd-gen IMiD |
| Haematologica |
Factors associated with left ventricular hypertrophy in children with sickle cell disease; results from the DISPLACE study The odds of LVH were higher among those on hydroxyurea compared to no therapy (OR: 1.83, 95% CI: 1.41 - 2.37). Overall results of the study showed that LVH occurs early in children with SCD and the risk increases with increasing age and with lower hemoglobin. Further, we found higher use of hydroxyurea among those with LVH, suggesting that the need for hydroxyurea conveys a risk of cardiovascular remodeling. |
Genomic determinants impacting the clinical outcome of mogamulizumab treatment for adult T-cell leukemia/lymphoma. Univariate analysis revealed that TP53, CD28 or CD274 alterations were associated with worse overall survival (OS hazard ratio [HR] 2.330, 95% confidence interval [CI], 1.183-4.589; HR 3.191, 95% CI, 1.287-7.911; HR 3.301, 95% CI, 1.130-9.641, respectively) but that CCR4 alterations were associated with better OS (HR 0.286, 95% CI, 0.087- 0.933). Multivariate analysis indicated that in addition to performance status, TP53, CCR4 or CD274 alterations (HR 2.467, 95% CI, 1.197-5.085; HR 0.155, 95% CI, 0.031-0.778; HR 14.393, 95% CI, 2.437-85.005, respectively) were independently and significantly associated with OS. The present study contributes to the establishment of precision medicine using mogamulizumab in ATL patients. |
Genotype-phenotype and outcome associations in patients with Fanconi anemia: The National Cancer Institute cohort. Overall median survival was 37 years; patients with leukemia or FANCD1/BRCA2 variants had poorest survival. Patients with variants in the upstream complex had better survival than ID or downstream complex (p=0.001 and 0.016, respectively). FA is phenotypically and genotypically heterogeneous; detailed characterization provides new insights towards understanding this complex syndrome and guiding clinical management. |
| J Hematol Oncol |
A proteolysis-targeting chimera molecule selectively degrades ENL and inhibits malignant gene expression and tumor growth. Compound 1 is a novel chemical probe for cellular and in vivo studies of ENL (including its oncogenic mutants) and a lead compound for further anticancer drug development. |
| Leukemia |
High expression level of ROR1 and ROR1-signaling associates with venetoclax resistance in chronic lymphocytic leukemia. Transduction of the CLL-cell-line MEC1 to express ROR1 enhanced expression of target genes induced by ROR1-signaling, increased expression of BCL-XL, and enhanced resistance to venetoclax, even in MEC1 made to express mutant forms of BCL2, which are associated with venetoclax resistance. Treatment of primary CLL cells with Wnt5a also increased their resistance to venetoclax, an effect that could be inhibited by the anti-ROR1 mAb (UC-961, zilovertamab). Collectively, these studies indicate that Wnt5a-induced ROR1-signaling can enhance resistance to venetoclax therapy. |
Immunoglobulin superfamily member 8 maintains myeloid leukemia stem cells through inhibition of ß-catenin degradation. At a molecular level, we found that activation of ß-catenin in LSCs depends on Igsf8, which promotes the association of FZD4 with its co-receptor LRP6 in the presence of Igsf8. Similarly, IGSF8 inhibition blocks the colony-forming ability of LSCs and improves the survival of recipients in xenograft models of myeloid leukemia. Collectively, these data indicate strong genetic evidence identifying Igsf8 as a key regulator of myeloid leukemia and the possibility that targeting IGSF8 may serve as a new therapeutic approach against myeloid leukemia. |
JAK3 mutations and mitochondrial apoptosis resistance in T-cell acute lymphoblastic leukemia. Inhibition of JAK3 led to loss of MEK, ERK and BCL2 phosphorylation, and BH3 profiling revealed that JAK3-mutant primary T-ALL patient samples were characterized by a dependence on BCL2. Treatment of JAK3-mutant T-ALL cells with the JAK3 inhibitor tofacitinib in combination with a spectrum of conventional chemotherapeutics revealed synergy with glucocorticoids, in vitro and in vivo. These findings thus provide key insights into the molecular genetics of mitochondrial apoptosis resistance in childhood T-ALL, and a compelling rationale for a clinical trial of JAK3 inhibitors in combination with glucocorticoids for patients with JAK3-mutant T-ALL. |
The outcome of patients with Hodgkin lymphoma and early relapse after autologous stem cell transplant has improved in recent years. The 4-year OS from BV, CPI, and SCT2 use was 55%, 48% and 55% respectively. In conclusion, the outcome after post-transplant relapse has improved significantly in recent years, particularly in the case of early relapse. These large-scale real-world data can serve as benchmark for future studies in this setting. |
| Thromb Haemost |
Enrichment of complement, immunoglobulins and autoantibody targets in the proteome of platelets from patients with Systemic Lupus Erythematosus (SLE). Platelets from SLE patients shared a specific protein profile, including immunoglobulins, complement proteins and autoantigens, largely independent of platelet size and in agreement with an integrated role for platelets in SLE. |
Plenty of the editorials are available as full text through the publisher website using the provided link
| Ann Oncol |
| Blood |
| Blood Cancer J |
Cutaneous manifestations of monoclonal gammopathy. These skin disorders can be associated with infiltration and proliferation of a malignant plasma cells or by a deposition of the monoclonal immunoglobulin in a nonmalignant monoclonal gammopathy. These disorders include POEMS syndrome, light chain amyloidosis, Schnitzler syndrome, scleromyxedema and TEMPI syndrome. This article provides a review of clinical manifestations, diagnostics criteria, natural evolution, pathogenesis, and treatment of these cutaneous manifestations. |
| J Hematol Oncol |
Emerging role of RNA sensors in tumor microenvironment and immunotherapy. Therefore, a comprehensive understanding of the roles of RNA sensors in TME could provide new insight into the antitumor immunotherapy. Moreover, RNA sensors could be prominent triggering targets to synergize with immunotherapies. In this review, we highlight the diverse mechanisms of RNA sensors in cancer immunity and their emerging contributions in cancer immunotherapy, including monotherapy with RNA sensor agonists, as well as combination with chemotherapy, radiotherapy, immune checkpoint blockade or cancer vaccine. |
Targeting regulated cell death (RCD) with small-molecule compounds in triple-negative breast cancer: a revisited perspective from molecular mechanisms to targeted therapies. More importantly, we demonstrate several small-molecule compounds (e. g., ONC201 and NCT03733119) by targeting the subroutines of RCD in TNBC clinical trials. Taken together, these findings will provide a clue on illuminating more actionable low-hanging-fruit druggable targets and candidate small-molecule drugs for potential RCD-related TNBC therapies. |
Letters to the editors and authors’ replies
| Am J Hematol |
| Ann Oncol |
| Blood Cancer J |
| J Hematol Oncol |
Targeting Fc BI-1206 sensitized the efficacy of rituximab monotherapy in a PDX model with triple resistance to rituximab, ibrutinib and CAR T-therapies (p |
all remaining publications eg case reports, images of the month, etc…
| Am J Hematol |
| Blood |
| Blood Adv |
| Leukemia |